title: A novel binuclear palladacycle complex inhibits melanoma growth in vitro and in vivo through apoptosis and autophagy.
abstract: Malignant melanoma is an aggressive skin cancer and it is reported to be the most treatment-resistant human cancer. Here we describe the anti-tumour activity of a novel binuclear palladacycle complex (AJ-5) in vertical growth phase (ME1402) and metastatic (WM1158) melanoma cell lines. We show that compared to normal control cell lines, AJ-5 is more effective in inhibiting the proliferation of ME1402 and WM1158 melanoma cells with IC50 values of 0.19 and 0.20μM, respectively. Flow cytometry analyses showed that AJ-5 induced apoptosis (sub-G1 peak) which was confirmed by Annexin V-FITC/propidium iodide double-staining, nuclear fragmentation and an increase in the levels of PARP cleavage. Furthermore, AJ-5 was shown to induce both intrinsic and extrinsic apoptotic pathways as measured by PUMA, Bax and active caspases. Interestingly, AJ-5 treatment also simultaneously induced the formation of autophagosomes and led to an increase in the autophagy markers LC3II and Beclin1. Inhibition of autophagy reduced AJ-5 cytotoxicity suggesting that AJ-5 induced autophagy was a cell death and not cell survival mechanism. Moreover we show that AJ-5 induces the ATM-CHK2 DNA damage pathway and that its anti-tumour function is mediated by the p38 and ERK1/2 signalling pathways. Importantly, AJ-5 treatment efficiently reduced tumour growth in melanoma bearing mice and induced high levels of autophagy and apoptosis markers. Together these findings suggest that AJ-5 may be an effective chemotherapeutic drug in the treatment of melanoma, a highly aggressive and intractable cancer.
authors.affiliation: Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, 7925 Cape Town, South Africa. Electronic address: saib.iwini@gmail.com.
authors.forename: Saeb
authors.initials: S
authors.lastname: Aliwaini
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Swarts
authors.forename: Angelique
authors.initials: A
authors.lastname: Blanckenberg
authors.forename: Selwyn
authors.initials: S
authors.lastname: Mapolie
authors.forename: Sharon
authors.initials: S
authors.lastname: Prince
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000473:pathology*; D010165:Palladium / Q000494:pharmacology*
chemical_list: D010165:Palladium
keywords: Apoptosis; Autophagy; Cell death; DNA damage; Melanoma; Palladium metallacycle